Endothelin receptor antagonists

Abstract

Novel N-phenyl imidazole derivatives, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists are described.

1 . A compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is H, C 1-6 alkyl or C 1-6 alkoxy;  
 R 2  is XR 5 , —R 8 CO 2 R 4 , —(CH 2 )XC(O)N(R 4 )S(O) y R 9 , —(CH 2 ) x S(O) y N(R 4 )C(O)R 9 , —(CH 2 ) x C(O)N(R 4 )C(O)R 9 , —(CH 2 ) n R 7 , —(CH 2 ) x S(O) y N(R 4 )S(O) y R 9  or Ar;  
 X is O, S or N 4 ;  
 R 3  is C 1-10 alkyl, XC 1-10 alkyl, Ar or XAr;  
 R 4  is hydrogen or C 1-6 alkyl;  
 R 5  is —R 8 CO 2 R 4 , —(CH 2 ) x C(O)N(R 4 )S(O) y R 9 , —(CH 2 ) x S(O) y N(R 4 )C(O)R 9 , —C(O)N(R 4 ) 2 , —(CH 2 ) x C(O)N(R 4 )C(O)R 9 , —(CH 2 ) n CO 2 R 4 , —(CH 2 ) x S(O) y N(R 4 )S(O) y R 9 , —(CH 2 ) n R 7 , or Ar;  
 R 6  is C 1-8 alkyl or —Ar;  
 P is tetrazol-5-yl, CO 2 R 4  or C(O)N(R 4 )S(O) y R 9 ;  
 R 7  is C 1-6  alkoxy, C 1-6 alkyl, hydroxy, —SC 1-6 alkyl, —NHSO 2 R 9 , SO 2 NHR 9 , —SO 3 H, —CO(NR 4 ) 2 , CN, —S(O) y C 1-6 alkyl, —PO(OR 4 ) 2 , —N(R 4 ) 2 , —NR 4 CHO, —NR 4 COC 1-6 alkyl, —NR 4 CON(R 4 ) 2  or Ar, or R 7  is tetrazolyl, which is substituted or unsubstituted by C 1-6 alkyl, CF 3  or C(O)R 3 ;  
 R 8  is C 1-4 alkylene, C 1-4 alkenylene or C 1-4 alkylidene, all of which may be linear or branched;  
 R 9  is C 1-10 alkyl, N(C 1-8 alkyl) 2  or Ar;  
 n is 1 to 4;  
 m is 0 to 3;  
 x is 0 to 4;  
 y is 1 or 2;  
 Ar is:  
                     
 naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, imidazolinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be substituted or unsubstituted by one or more Z 1  or Z 2  groups;  
 Z 1  and Z 2  are independently hydrogen, XR 4 , C 8 alkyl, CO 2 R 4 , C(O)N(R 4 ) 2 , CN, NO 2 , F, Cl, Br, I, N(R 4 ) 2 , NHC(O)R 4  or tetrazolyl which may be substituted or unsubstituted by C 1-6 alkyl, CF 3  or C(O)R 4 ;  
 A is C═O or [C(R 4 ) 2 ] q ;  
 B is —CH 2 — or —O—; and  
 q is 1 or 2:  
 and the dotted line indicates the optional presence of a double bond;  
 or a pharmaceutically acceptable salt thereof;  
 provided.  
 R 6  is not thienyl; and  
 R 2  is not (CH) n C 1-6  alkyl, or —CH═CHCO 2 R 4 .  
 
     
     
         2 . A compound of  claim 1  wherein there is an optional double bond present; R 4  is cis to P; R 1  is H or C 1-6 alkoxy; R 2  is —OR 5 , —R 8 CO 2 H, —(CH 2 ) x C(O)N(R 4 )S(O) y R 9 , —(CH 2 ) x C(O)NHC(O)R 9 , —(CH 2 ) n R 7 , or R 2  is phenyl or pyridyl, both of which may be substituted or unsubstituted by one or more Z 1  or Z 2  groups; R 3  is C 1-10 alkyl, C 1-10 alkoxy or R 3  is phenyl or pyrazolyl, both of which may be substituted or unsubtituted by C 1-6  alkoxy, Cl, Br, F or I; R 4  is hydrogen or C 1-6 alkyl; R 5  is —R 8 CO 2 H, —(CH 2 ) x C(O)N(R 4 )S(O) y R 9 , —(CH 2 ) x C(O)NHC(O)R 9 , —(CH 2 ) n CO 2 R 4 . —(CH 2 ) n R 7  or pyridyl which may be substituted or unsubstituted by Z 1 ; R 6  is (a), (b) or indolyl; P is CO 2 H or C(O)NHS(O)yRg; R 7  is C 1-6  alkoxy, C 1-6 alkyl, piperidinyl, hydroxy, —NHSO 2 R 9 , —CONH, —N(R 4 ) 2 , —NR 4 CON(R 4 ) 2  or R 7  is thienyl, pyridyl, pyrimidyl, phenyl, all of which may be substituted or unsubstituted by one or more Z 1  or Z 2  groups or R 7  is tetrazol-5-yl or piperazinyl both of which are substituted or unsubstituted by C 1-6 alkyl; R 8  is C 1-4 alkenylene which may be linear or branched; R 9  is C 1-10 alkyl, N(C 1-8 alkyl) 2  or phenyl which may be substituted or unsubstituted by C 1-8 alkyl; n is 1 to 4; m is 1; x is 0 to 4; y is 1 or 2; Z 1  and Z 2  are independently hydrogen, hydroxy, C 1-8 alkyl, C 1-6 alkoxy, CO 2 H, C(O)N(R 4 ) 2 , F, Cl, Br, I, N(R 4 ) 2 , or tetrazolyl which may be substituted or unsubstituted by C 1-6 alkyl; A is [C(R 4 ) 2 ] q ; q is 1; and B is —O—.  
     
     
         3 . A compound of  claim 2  wherein there is an optional double bond present; R 4  is cis to P; R 1  is H or C 1-3 alkoxy; R 2  is —(CH 2 ) x C(O)NHS(O) 2 R 9 , —OR 5  —O(CH 2 ) 1-3 CO 2 H or —(CH 2 ) n R 7 ; R 3  is C 1-5 alkyl; R 4  is hydrogen; R 5  is —(CH 2 ) x C(O)NHS(O) 2 R 9 , —(CH 2 ) x C(O)NHC(O)R 9 , —(CH 2 ) n R 7  or pyridyl which may be substituted or unsubstituted by Z 1 ; R 6  is (b); P is CO 2 H; R 7  is hydroxy, —NHSO 2 R 9 , —CONH(C 1-5 alkyl), or R 7  is tetrazol-5-yl or piperazinyl, both of which may be substituted or unsubstituted by C 1-6 alkyl or R 7  is thienyl, pyridyl, pyrimidyl, or phenyl, all of which may be substituted or unsubstituted by one or more Z 1  or Z 2  groups; R 9  is C 1-5 alkyl, N(C 1-5 alyl) 2  or R 9  is phenyl which may be substituted or unsubstituted by C 1-5 alkyl; n is 1 to 4; m is 1; x is 0 to 4; Z 1  and Z 2  are independently hydrogen, hydroxy, C 1-6 alkoxy, CO 2 H, C(O)NH 2 , F, Cl, or tetrazolyl which may be substituted or unsubstituted by C 1-6 alkyl; A is —CH 2 —; and B is —O—.  
     
     
         4 . A compound of  claim 1  chosen from the group consisting of: 
 (E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 (E)-3-[2-Butyl-1-[2-(4-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-(3-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-[N-(2-methylphenyl)sulfonyl]carboxamidomethoxy-4-methoxyl phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-[N-(4-methylphenyl)sulfonyl]carboxamidomethoxy-4-methoxy] phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-(N-dimethylaminosulfonyl)carboxamidomethoxy-4-methoxy]phenyl-1H-irruidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-(N-methanesulfonyl)carboxanridomethoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-(N-t-butylsulfonyl)carboxamidomethoxy-4methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-(N-1-propylsulfonyl)carboxamidomethoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-(2-(tetrazol-5-yl)benzyloxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-(2ethyl-3H-tetrazol-5-yl)benzyloxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
 E-3-[2-Butyl-1-[2-[(4-carboxypyridin-3-yl)oxy]4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(3,4-methylenedioxyphenyl)methyi]-2-propenoic acid;  
 (E)-3-[2-Butyl-[1-(2-carboxymethoxy)-4-methoxy)phenyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid; or  
 E-3-[2-Butyl-1-[2-(3-carboxy)propoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid.  
 
     
     
         5 . A compound of  claim 1  which is (E)-3-[2-Butyl-1-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-irridazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;  
     
     
         6 . A compound of  claim 2  which is (E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)]carboxamidomeltoxy-4-methoxyphenyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoic acid dipotassium;  
     
     
         7 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         8 . A compound of  claim 1  for use as an endothelin receptor antagonist.  
     
     
         9 . A method of treatment of diseases caused by an excess of endothelin comprising administering to a subject in need thereof, an effective amount of an endothelin receptor antagonist of  claim 1 .  
     
     
         10 . A method of treating hypertension, renal failure or cerbrovascular disease which comprises administering to a subject in need thereof, an effective amount of a compound of  claim 1 .  
     
     
         11 . A method for the prophylaxis and treatment of radiocontrast induced renal failure which comprises administering to a subject in need thereof, an effective amount of a compound of  claim 1 .  
     
     
         12 . A method of treatment of benign prostatic hypertrophy which comprises administering to a subject in need thereof, an effective amount of a compound of  claim 1 .  
     
     
         13 . A method of treatment of congestive heart failure which comprises administering to a subject in need thereof, an effective amount of a compound of  claim 1 .  
     
     
         14 . A method of treatment of migraine which comprises administering to a subject in need thereof, an effective amount of a compound of  claim 1 .  
     
     
         15 . A method of preventing or treating restenosis which comprises administering to a subject in need thereof, an effective amount of a compound of  claim 1 .  
     
     
         16 . A method of treatment of pulmonary hypertension which comprises administering to a subject in need thereof, an effective amount of a compound of  claim 1.